| LMTK3 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | LMTK3, LMR3, PPP1R101, TYKLM3, lemur tyrosine kinase 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | MGI: 3039582; HomoloGene: 79449; GeneCards: LMTK3; OMA:LMTK3 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Lemur tail kinase 3 is a protein that in humans is encoded by the LMTK3 gene.
LMTK3 is often overexpressed in human cancers where it promotes tumour growth, invasion and metastasis and therapy resistance. It was first identified in 2011 through a kinase screen of regulators of ERα by Giamas et al. who found that it promotes upregulation of ERα through PKC inhibition and inhibits ERα degradation through direct phosphorylation of ERα. Numerous other studies have linked LMTK3 to cancer in glioblastoma, non-small cell lung cancer, thyroid malignancies and bladder cancer, among others. A small molecule inhibitor, C28, has now been developed for LMTK3 which shows potent anti-cancer activity in vitro and in vivo.
Function
The most well-characterised physiological role of LMTK3 is in the central nervous system. LMTK3 is expressed in the cerebral cortex, striatum, cerebellum, hippocampus, olfactory bulb and tubercle. LMTK3 knockout mice are more hyperactive and show less signs of anxiety than wild-type counterparts. In addition, the mice showed lower levels of depression-like behaviour in forced swim tests and tail suspension assays. LMTK3 knockout mice also have cognitive impairments and show behaviour related to schizophrenia and bipolar disorder. This may be due to impairment in GluA1 trafficking in neurons. These studies show that LMTK3 plays an important role in the central nervous system.
Clinical significance
LMTK3 is implicated in a number of human cancers as an oncogene as well as a potential predictive or prognostic biomarker. The most well-known role of LMTK3 is in ERα signalling. In 2011, Giamas et al. showed that LMTK3 is a potent regulator of ERα through a kinome-wide siRNA screen. By examining the effect of depletion of different genes of the expression of an ERα-regulated gene, they showed that LMTK3 knockdown significantly reduces ERα activity. LMTK3 phosphorylates ERα, increasing stability and protecting ERα from proteasomal degradation. LMTK3 also inhibits PKC, reducing AKT activity and therefore allowing accumulation of FoxO3 in cells, lifting inhibition of ESR1 transcription, causing an increase in ERα expression. An in vivo model also showed that LMTK3 siRNA reduces tumour growth in mice injected with MCF7 ER+ cells. Later analyses of clinical data show that LMTK3 is predictive and prognostic in breast cancer. High nuclear and cytoplasmic staining in breast cancer cells for LMTK3 is associated with poor clinical outcomes .
LMTK3 is also associated with endocrine resistance in breast cancer. Stebbing et al. showed that LMTK3 regulates a number of genes involved in tamoxifen resistance. LMTK3 overexpression also promotes chemotherapy resistance in breast cancer cells.
Later, another study by Giamas' group revealed that LMTK3 is strongly associated with cell invasiveness and metastasis through regulation of integrin subunits. LMTK3 acts through GRB2, inducing RAS activation and CDC42 activation, leading to increased ITGA5 and ITGB1 expression through the transcription factor, serum response factor (SRF). The group also showed that LMTK3 has nuclear roles where is facilitates the interaction between KAP1 (Krüppel-associated box domain-associated protein 1) and a KAP1 phosphatase, PP1α (protein phosphatase 1α). This results in trimethylation of Histone H3 lysine 9 (H3K9me3) at tumour suppressor-like genes, resulting in silencing and a downregulation of tumour suppressors in breast cancer.
Giamas' group discovered the small molecule inhibitor, C28 in 2020 which is a potent, selective inhibitor of LMTK3. C28 is an orally available and highly selective ATP-competitive inhibitor of LMTK3. Data from the NCI-60 cell line panel and experiments in xenografts show that the drug is an effective inhibitor of breast cancer growth in vivo. LMTK3 is an HSP90-CDC37 client protein which requires this interaction for folding and stability. C28 is a competitive inhibitor of LMTK3 that also deprives LMTK3 of HSP90, promoting instability and degradation of LMTK3. More recently, another compound, C36 has been characterised as a selective inhibitor of LMTK3 with apoptosis-promoting properties in breast cancer cells.
References
- ^ GRCh38: Ensembl release 89: ENSG00000142235 – Ensembl, May 2017
- ^ GRCm38: Ensembl release 89: ENSMUSG00000062044 – Ensembl, May 2017
- "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Ditsiou A, Gagliano T, Samuels M, Vella V, Tolias C, Giamas G (September 2021). "The multifaceted role of lemur tyrosine kinase 3 in health and disease". Open Biology. 11 (9): 210218. doi:10.1098/rsob.210218. PMC 8478525. PMID 34582708.
- Wendler F, Purice TM, Simon T, Stebbing J, Giamas G (September 2021). "The LMTK-family of kinases: Emerging important players in cell physiology and pathogenesis" (PDF). Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1867 (9): 165372. doi:10.1016/j.bbadis.2018.12.023. PMID 30597196.
- ^ Giamas G, Filipović A, Jacob J, Messier W, Zhang H, Yang D, et al. (June 2011). "Kinome screening for regulators of the estrogen receptor identifies LMTK3 as a new therapeutic target in breast cancer". Nature Medicine. 17 (6): 715–719. doi:10.1038/nm.2351. PMID 21602804. S2CID 5279914.
- Fazi B, Felsani A, Grassi L, Moles A, D'Andrea D, Toschi N, et al. (September 2015). "The transcriptome and miRNome profiling of glioblastoma tissues and peritumoral regions highlights molecular pathways shared by tumors and surrounding areas and reveals differences between short-term and long-term survivors". Oncotarget. 6 (26): 22526–22552. doi:10.18632/oncotarget.4151. PMC 4673180. PMID 26188123.
- Xu Z, Qi X, Zhang X, Yu L (May 2014). "Preoperative serum LMTK3 as a novel biomarker in non-small cell lung cancer". Tumour Biology. 35 (5): 5007–5011. doi:10.1007/s13277-014-1660-3. PMID 24510346. S2CID 14656556.
- Lu L, Yuan X, Zhang Q, Zhang H, Shen B (April 2017). "LMTK3 knockdown retards cell growth and invasion and promotes apoptosis in thyroid cancer". Molecular Medicine Reports. 15 (4): 2015–2022. doi:10.3892/mmr.2017.6262. PMC 5364963. PMID 28260052.
- Jiang T, Lu X, Yang F, Wang M, Yang H, Xing N (October 2020). "LMTK3 promotes tumorigenesis in bladder cancer via the ERK/MAPK pathway". FEBS Open Bio. 10 (10): 2107–2121. doi:10.1002/2211-5463.12964. PMC 7530379. PMID 32865871.
- Kawa S, Fujimoto J, Tezuka T, Nakazawa T, Yamamoto T (March 2004). "Involvement of BREK, a serine/threonine kinase enriched in brain, in NGF signalling". Genes to Cells. 9 (3): 219–232. doi:10.1111/j.1356-9597.2004.00714.x. PMID 15005709.
- Inoue T, Hoshina N, Nakazawa T, Kiyama Y, Kobayashi S, Abe T, et al. (April 2014). "LMTK3 deficiency causes pronounced locomotor hyperactivity and impairs endocytic trafficking". The Journal of Neuroscience. 34 (17): 5927–5937. doi:10.1523/JNEUROSCI.1621-13.2014. PMC 6608282. PMID 24760852.
- Montrose K, Kobayashi S, Manabe T, Yamamoto T (August 2019). "Lmtk3-KO Mice Display a Range of Behavioral Abnormalities and Have an Impairment in GluA1 Trafficking". Neuroscience. 414: 154–167. doi:10.1016/j.neuroscience.2019.06.033. PMID 31310731. S2CID 195937172.
- Stebbing J, Filipovic A, Ellis IO, Green AR, D'Silva TR, Lenz HJ, et al. (April 2012). "LMTK3 expression in breast cancer: association with tumor phenotype and clinical outcome". Breast Cancer Research and Treatment. 132 (2): 537–544. doi:10.1007/s10549-011-1622-z. PMID 21671015. S2CID 19222468.
- Stebbing J, Filipovic A, Lit LC, Blighe K, Grothey A, Xu Y, et al. (July 2013). "LMTK3 is implicated in endocrine resistance via multiple signaling pathways". Oncogene. 32 (28): 3371–3380. doi:10.1038/onc.2012.343. PMID 22869149.
- Stebbing J, Shah K, Lit LC, Gagliano T, Ditsiou A, Wang T, et al. (June 2018). "LMTK3 confers chemo-resistance in breast cancer". Oncogene. 37 (23): 3113–3130. doi:10.1038/s41388-018-0197-0. PMC 5992129. PMID 29540829.
- Xu Y, Zhang H, Lit LC, Grothey A, Athanasiadou M, Kiritsi M, et al. (June 2014). "The kinase LMTK3 promotes invasion in breast cancer through GRB2-mediated induction of integrin β₁". Science Signaling. 7 (330): ra58. doi:10.1126/scisignal.2005170. PMID 24939894. S2CID 7831460.
- Xu Y, Zhang H, Nguyen VT, Angelopoulos N, Nunes J, Reid A, et al. (August 2015). "LMTK3 Represses Tumor Suppressor-like Genes through Chromatin Remodeling in Breast Cancer". Cell Reports. 12 (5): 837–849. doi:10.1016/j.celrep.2015.06.073. hdl:10044/1/33933. PMID 26212333.
- Ditsiou A, Cilibrasi C, Simigdala N, Papakyriakou A, Milton-Harris L, Vella V, et al. (November 2020). "The structure-function relationship of oncogenic LMTK3". Science Advances. 6 (46). Bibcode:2020SciA....6.3099D. doi:10.1126/sciadv.abc3099. PMC 7673765. PMID 33188023.
- Agnarelli A, Lauer Betrán A, Papakyriakou A, Vella V, Samuels M, Papanastasopoulos P, et al. (January 2023). "The Inhibitory Properties of a Novel, Selective LMTK3 Kinase Inhibitor". International Journal of Molecular Sciences. 24 (1): 865. doi:10.3390/ijms24010865. PMC 9821308. PMID 36614307.